The most highly evolved structure in our brain is the neo-cortex. Our rich behavioral repertoire and complex abilities are possible because of the neo-cortex. All sensory information, except olfaction, feeds the neo-cortex basically through a single structure called thalamus. Neo-cortex and thalamus are recurrently and extensively interconnected through thalamocortical and corticothalamic pathways. Thus, these pathways form neural circuits that are essential for the acquisition, processing and storage of information, and if they go awry all neo-cortical processing will be jeopardized. The impact of even minor problems in information transmission through these neural circuits is potentially devastating. The hypothesis presented in the present grant proposal is that when certain parts of our neo-cortex and thalamus are being used behaviorally (e.g. the auditory cortex during a concert) the pathways between these structures, representing the relevant modality, have different properties than when they are not engaged behaviorally (e.g. the auditory cortex when you are in a quiet room). This seems to be due to neuromodulators that are released in neo-cortex and thalamus during behavioral engagement. These neurotransmitters modulate cellular, synaptic and network mechanisms, transforming the properties of these pathways to allow the effective transfer, processing, and storage of information. The aim of the present proposal is to study the properties of pathways in the thalamocortical system, to investigate how neuromodulators affect these pathways and to find out how these mechanisms work during information processing and behavioral engagement. The pathways that we will initially concentrate on are the primary sensory input to the somatosensory thalamus (lemniscal pathway) and the massive input to the thalamus from the neo-cortex (corticothalamic pathway). Our approach is multifaceted. Studies in slices will tease apart the basic properties of lemniscal and corticothalamic synapses and how they are affected by specific neuromodulators. Studies using anesthetized animals in vivo will explore how these properties function to produce sensory transmission. Studies in freely behaving animals will reveal how the properties of these pathways are regulated during behavioral state. Understanding how these pathways are regulated during normal behavior is an indispensable first step to comprehend how these pathways, and thus information processing, are altered in several psychiatric and neurological disorders.